Polymorphism of Genes and Implantation Failure

Implantation failure is the most frequent cause of pregnancy loss in couples who try to conceive, either in a natural way or using assisted reproductive techniques (ART). Identify the precise mechanisms of implantation failure can lead to identify couples at risk and also providing appropriate therapeutic options to affected couples. Despite the high prevalence of this disorder, a few causing factors are demonstrated so far. Recent studies indicate that genetic factors play an important role in the occurrence of recurrent implantation failure. Although some of these factors, such as numerical chromosomal aneuploidy are known to be causative factors, there are some other factors that solely increase susceptibility to this event. In the present review we try to list the genetic polymorphisms that are known as susceptibility factors in implantation failure.

. Furthermore single gene disorders seem to be important factor in pregnancy loss, as our previous results show that there is a correlation between consanguineous marriage and the occurrence of idiopathic spontaneous fetal loss (2).
Since about 80% of pregnancies are lost during the first trimester, it has been postulated that the major cause of failed pregnancy is an error of embryo implantation (3).
Genetic factors that lead to implantation failure have overlap with those involved in recurrent spontaneous abortion and infertility (4)(5)(6).
Implantation failure is the most frequent cause of lack of pregnancy after in vitro fertilization (IVF) and embryo transfer, as implantation failure takes place in approximately 40% of IVF experiments (3). Successful implantation requires trophoblastic growth, invasion into the endometrium and stimulation of vascularization to provide its own blood supply (4)(5)(6). Several studies performed in recent decade indicate that p53 has a critical role in maternal reproduction (7,8). While p53 -/male mice show normal reproduction rate, p53 -/female mice show reduced pregnancy ability and litter size when mated with p53 -/-, p53 -/+ and p53 +/+ male mice and worst pregnancy rate and litter size in mating with p53 -/male mice (9). It has been suggested that P53 activates embryo implantation into the uterus as a Functional studies revealed that this polymorphism modifies the P53 transcriptional activity and show association with cancer susceptibility (11).
Furthermore this SNP has approved effects on immune system and also chemoresistance of tumor cells (12)(13)(14).
P72 allele is significantly more common than R72 between women with recurrent implantation failure (15)(16)(17). Two most accepted explanations offered are: 1) impact of this allele on the expression levels of LIF factor and 2) effect of this allele on maternal immune system function against implanting embryo.
Several studies show that maternal immune system has an immune tolerance against implanting embryo but as has proven, P72 allele has an association with autoimmune disorders such as lupus erythematosis and arthritis rheumatoid (14). It is possible that presence of P72 allele may sensitize maternal immune system against implanting embryo and lead to embryo rejection.
Expression analysis of cellular models bearing either of these tow alleles reveal that P72 allele induces leukemia inhibiting factor (LIF) expression two fold lower than R72 allele (18)(19).
As will be explained, LIF has an improved effect on the success rate of pregnancy (20).

Leukemia inhibiting factor (LIF)
The human LIF gene plays an essential role in embryo implantation. Expression of LIF is continuous in the uterus however it shows a transient expression peak during pregnancy and this peak coincides with the onset of implantation. However, other polymorphisms of p53 pathway in Iranian population remain to be investigated .

P53 pathway independent genes
In addition to p53 pathway members, there are several other genes which are implicated in embryo implantation. Majority of these genes are involved in invasion of embryo into endometrium and also in pregnancy hormonal homeostasis.

2) gene
Cox-2 enzyme encoded by PTGS-2 gene, is an inducible enzyme in prostaglandin construction pathway which is induced by a range of stimuli such as growth factors and mitogens (11).
Studies on the expression pattern of Cox isoforms in the preimplantation mouse uterus indicate the role of these enzymes in embryo implantation (11). Furthermore, studies on cox-2 -/mice indicate an impaired angiogenesis into the implantation site (55). Ptgs2 mutation leads to multiple defects in the reproductive process including implantation (56). In human, expression level of COX-2 in RIF and infertile women decreases in comparison to healthy controls (57).
Given these results, the association between the promoter polymorphism -765G> C and RIF were evaluated and the results showed that -765C allele is associated with increased risk of RIF (58).

Mucin-4 (MUC-4) gene
The most critical step in embryo implantation is adhesion of outer trophectoderm layer of the blastocyst into the luminal epithelium (74)(75)(76)(77). This process is dependent on expression of adhesion molecules and suppression of anti adhesion molecules expression (22). Mucins are important group of adhesion molecules that show a wide range of tissue expression (78). Among mucin molecules, Muc-4 is an interesting candidate to explore because of its high expression level in endometrial epithelium (79).
Muc-4 has an important role in invasion of human cytotrophoblasts into endometrium (80).
Since lubricating function of muc-4 in lubricating of reproductive tracts it hypothesized, those different-size alleles of muc-4, resulting from VNTR polymorphisms of this gene, affect receptivity of endometrium and implantation success rate (81). However Koscinski et al. findings suggest that the different-sized muc-4 alleles do not interfere with implantation (82). Interestingly, other genetic variants of muc-4 were found to be correlated with endometriosis related infertility (81).

Conclusion
According to the presented data, implanting embryo behave as a tumor against endometrium.
Invasion and angiogenesis are critical steps in this process. By genotyping of RIF suffered couples we can predict the risk of IVF failure and present appropriate therapeutic options.